Multifunctional ICG‐SB@Lip‐ZA Nanosystem Focuses on Remodeling the Inflammatory‐Immunosuppressive Microenvironment After Photothermal Therapy to Potentiate Cancer Photothermal Immunotherapy

Abstract Achieving full eradication of residual tumors post photothermal therapy (PTT) hinges on the immune system's activation and response. Nevertheless, the resultant local inflammation attracts a significant influx of aberrant immune cells and fibroblasts, such as tumor‐associated macrophages (TAMs) and cancer‐associated fibroblasts (CAFs), following tumor PTT. This phenomenon exacerbates immune evasion and the persistence of residual tumor cells, culminating in tumor recurrence and advancement. To tackle this challenge, a combined therapeutic approach utilizing multifunctional ICG‐SB@Lip‐ZA nanosystem has been introduced. Indocyanine green (ICG) as a photothermal‐transducer ablated tumor cells, zoledronic acid (ZA) depletes TAMs recruited by the inflammatory tumor microenvironment (mostly M2‐like phenotype), SB‐505124 affects CAFs proliferation in the tumor microenvironment (TME) by inhibiting the transforming growth factor‐β （TGF‐β） pathway, thereby removing physical barriers to T cell infiltration. In a breast cancer model, these immunomodulatory nanoliposomes markedly decrease the population of M2‐like TAMs in the TME, eliminate physical barriers hindering T cell infiltration, reshape the inflammatory immune‐suppressive tumor microenvironment, eventually leading to a rate of tumor eradication of 94%. This multifunctional ICG‐SB@Lip‐ZA nanosystem (including photothermal conversion, TAM depletion, and TGF‐β pathway blockade) offers a promising strategy for mitigating the deteriorating tumor microenvironment following PTT and presents a more efficient approach for clinical photothermal‐immune combination therapy.